> Table of Contents > Erythema Nodosum
Erythema Nodosum
Faruq Pradhan, MBBCh
Fredric D. Gordon, MD, AGAF
image BASICS
DESCRIPTION
  • A delayed-type hypersensitivity reaction to various antigens, or an autoimmune reaction presenting as a panniculitis that affects subcutaneous fat
  • Clinical pattern of multiple, bilateral, erythematous, tender nodules in a typically pretibial distribution that undergo a characteristic pattern of color changes, similar to that seen in bruises. Unlike erythema induratum, the lesions of erythema nodosum (EN) do not typically ulcerate.
  • Occurs most commonly on the shins; less commonly on the thighs, forearms, trunk, head, or neck
  • Often associated with nonspecific prodrome including fever, weight loss, and arthralgia
  • Often idiopathic but may be associated with a number of clinical entities
  • Usually remits spontaneously in weeks to months without scarring, atrophy, or ulceration
  • Uncommon to have recurrences after initial presentation
Pregnancy Considerations
May have repeat outbreaks during pregnancy
Pediatric Considerations
Rare pediatric variant has lesions only on palms or soles, often unilateral. Typically has a shorter duration in children than adults.
EPIDEMIOLOGY
Incidence
  • 1 to 5/100,000/year
  • Predominant age: 20 to 30 years
  • Predominant sex: female > male (6:1) in adults
Prevalence
Varies geographically depending on the prevalence of disorders associated with EN
ETIOLOGY AND PATHOPHYSIOLOGY
  • Idiopathic: up to 55%
  • Infectious: 44%. Streptococcal pharyngitis (most common), mycobacteria, mycoplasma, chlamydia, mycoplasma, coccidiodomycosis, rarely can be caused by Campylobacter spp., ricketssiae, Salmonella spp., psittacosis, syphilis
  • Sarcoidosis: 11-25%
  • Drugs: 3-10%. Sulfonamides, amoxicillin, oral contraceptives, bromides, azathioprine, vemurafenib
  • Pregnancy: 2-5%,
  • Enteropathies: 1-4%. Ulcerative colitis, Crohn disease, Behçet disease, celiac disease, diverticulitis
  • Rare causes: <1% (1)
    • Fungal: dermatophytes, coccidioidomycosis, histoplasmosis, blastomycosis
    • Viral/chlamydial: infectious mononucleosis, lymphogranuloma venereum, paravaccinia, HIV
    • Malignancies: lymphoma/leukemia, sarcoma, myelodysplastic syndrome
    • Sweet syndrome
RISK FACTORS
See “Etiology and Pathophysiology.”
COMMONLY ASSOCIATED CONDITIONS
See “Etiology and Pathophysiology.”
image DIAGNOSIS
PHYSICAL EXAM
  • Lesions initially present as warm, tender, erythematous firm nodules and become fluctuant, gradually fading to resemble a bruise over 1 to 2 months (erythema contusiformis).
  • Typically pretibial, although can extend proximally to involve thighs or trunk (atypically can involve extensor surface of forearms)
  • Diameter varies from 1 to 10 cm with poor demarcation.
DIFFERENTIAL DIAGNOSIS
  • Nodular vasculitis or erythema induratum (warm ulcerating calf nodules)
  • Superficial thrombophlebitis
  • Cellulitis
  • Weber-Christian disease (violaceous, scarring nodules)
  • Lupus panniculitis
  • Cutaneous polyarteritis nodosa
  • Sarcoidal granulomas
  • Cutaneous T-cell lymphoma
  • EN leprosum (clinically similar to EN but shows vasculitis on histopathology)
  • Subcutaneous infection (including staphylococcus, Sporothrix schenckii, Nocardia brasiliensis, Mycobacterium marinum, Leishmania braziliensis)
DIAGNOSTIC TESTS & INTERPRETATION
Diagnosis is made clinically, with support of testing
  • ESR or C-reactive protein (CRP): often elevated, but can be normal in up to 40% (2)[C]
  • CBC: mild leukocytosis (2)[C]
  • Urine pregnancy test (2)[C]
  • Throat culture, antistreptolysin O titer (2)[C]
  • Blood and/or stool culture, stool ova and parasites (O&P)
  • Tuberculin skin testing (2)[C]
  • Seronegative rheumatoid factor
Initial Tests (lab, imaging)
CXR for hilar adenopathy or infiltrates related to sarcoidosis or tuberculosis (2)[C]
Diagnostic Procedures/Other
Deep-incisional or excisional skin biopsy including subcutaneous tissue; rarely necessary except in atypical cases with ulceration, duration >12 weeks, or absence of nodules overlying lower limbs (3)[C]
Test Interpretation
  • Septal panniculitis without vasculitis
  • Neutrophilic infiltrate in septa of fat tissue early in course
  • Actinic radial (Miescher) granulomas, consisting of collections of histocytes around a central stellate cleft, may be seen.
  • Fibrosis, paraseptal granulation tissue, lymphocytes, and multinucleated giant cells predominate late in course (4).
image TREATMENT
  • Condition usually self-limited within 1 to 2 months
  • All medications listed as treatment for EN are offlabel uses of the medications. There are no specific FDA-approved medications.
P.363

GENERAL MEASURES
  • Mild compression bandages and leg elevation may reduce pain. (Wet dressings, hot soaks, and topical medications are not useful.)
  • Discontinue potentially causative drugs.
  • Treat underlying disease.
  • Indication for treatment is poorly defined in literature; hence, therapy specifically for EN is directed towards symptom management.
MEDICATION
First Line
  • NSAIDs:
    • Ibuprofen 400 mg PO q4-6h (not to exceed 3,200 mg/day)
    • Indomethacin 25 to 50 mg PO TID
    • Naproxen 250 to 500 mg PO BID
  • Precautions
    • GI upset/bleeding (avoid in Crohn or ulcerative colitis)
    • Fluid retention
    • Renal insufficiency
    • Dose reduction in elderly, especially those with renal disease, diabetes, or heart failure
    • May mask fever
    • NSAIDs can increase cardiovascular (CV) risk.
  • Significant possible interactions
    • May blunt antihypertensive effects of diuretics and &bgr;-blockers
    • NSAIDs can elevate plasma lithium levels.
    • NSAIDs can cause significant elevation and prolongation of methotrexate levels.
Second Line
  • Potassium iodide 400 to 900 mg/day divided BID or TID for 3 to 4 weeks (for persistent lesions); need to monitor for hyperthyroidism with prolonged use; pregnancy class D (5)[B]
  • Corticosteroids for severe, refractory, or recurrent cases in which an infectious workup is negative. Prednisone 1 mg/kg/day for 1 to 2 weeks is the recommended dose/duration. Potential side effects include hyperglycemia, hypertension, weight gain, worsening gastroesophageal reflux disease, mood changes, bone loss, osteonecrosis, and proximal myopathy (1)
  • For EN related to Behçet disease, one can also consider colchicine 0.6 to 1.2 mg BID. Potential side effects include GI upset and diarrhea (6)[B].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Occasionally, admission may be needed for the antecedent illness (e.g., tuberculosis).
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Keep legs elevated
  • Elastic wraps or support stockings may be helpful when patients are ambulating.
Patient Monitoring
Monthly follow-up or as dictated by underlying disorder
DIET
No restrictions
PATIENT EDUCATION
  • Lesions will resolve over a few weeks to months
  • Scarring is unlikely.
  • Joint aches and pains may persist.
  • <20% recur
PROGNOSIS
  • Individual lesions resolve generally within 2 weeks.
  • Total time course of 6 to 12 weeks but may vary with underlying disease.
  • Joint aches and pains may persist for years.
  • Lesions do not scar.
  • Recurrences: occurs over variable periods, averaging several years; seen most often in sarcoid, streptococcal infection, pregnancy, and oral contraceptive use. If medication induced, avoid recurrent exposure.
REFERENCES
1. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75(5):695-700.
2. Cribier B, Caille A, Heid E, et al. Erythema nodosum and associated diseases. A study of 129 cases. Int J Dermatol. 1998;37(9):667-672.
3. Requena L, Yus ES. Erythema nodosum. Dermatol Clin. 2008;26(4):425-438.
4. Sánchez Yus E, Sanz Vico MD, de Diego V. Miescher's radial granuloma. A characteristic marker of erythema nodosum. Am J Dermatopathol. 1989;11(5):434-442.
5. Horio T, Imamura S, Danno K, et al. Potassium iodide in the treatment of erythema nodosum and nodular vasculitis. Arch Dermatol. 1981;117(1): 29-31.
6. Yurdakul S, Mat C, Tüzün Y, et al. A double-blind trial of colchicine in Behçet's syndrome. Arthritis Rheum. 2001;44(11):2686-2692.
Additional Reading
&NA;
  • Bartyik K, Várkonyi A, Kirschner A, et al. Erythema nodosum in association with celiac disease. Pediatr Dermatol. 2004;21(3):227-230.
  • Chong TA, Hansra NK, Ruben BS, et al. Diverticulitis: an inciting factor in erythema nodosum. J Am Acad Dermatol. 2012;67(1):e60-e62.
  • Harris T, Henderson MC. Concurrent Sweet's syndrome and erythema nodosum. J Gen Intern Med. 2011;26(2):214-215.
  • Jeon HC, Choi M, Paik SH, et al. A case of assisted reproductive therapy-induced erythema nodosum. Ann Dermatol. 2011;23(3):362-364.
  • Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75(5):695-700.
  • Then C, Langer A, Adam C, et al. Erythema nodosum associated with myelodysplastic syndrome: a case report. Onkologie. 2011;34(3):126-128.
Codes
&NA;
ICD10
  • L52 Erythema nodosum
  • A18.4 Tuberculosis of skin and subcutaneous tissue
Clinical Pearls
&NA;
  • Lesions of EN appear to be erythematous patches, but when palpated, their underlying nodularity is appreciated.
  • Evaluation for a concerning underlying etiology is necessary in EN, but most cases are idiopathic.
  • EN in the setting of hilar adenopathy may be seen with multiple etiologies and does not exclusively indicate sarcoidosis.
  • In patients with a history of Hodgkin lymphoma, EN may be an early sign of recurrence.